Engineering immune responses will enable achievement of the true potential of the next generation of medical treatments by addressing the significant barrier of the host response. The central role of dendritic cells (DCs) as gatekeepers to the initiation of immune responses and maintenance of tolerance renders the control of their phenotype particularly important in situations where immune responses can be harnessed in combination products, such as vaccine delivery systems or tissue engineering strategies. Using biomaterials, an integral component of these devices, to direct the host response is a powerful and visionary strategy. Babensee et al have demonstrated biomaterial-based control of DC phenotype with modulation of immune responses to co- delivered antigen in vivo. As such, DCs at opposite ends of the phenotypic spectrum, from immature (or tolerogenic) to mature, are desirable to either induce non-responsiveness /tolerance or enhance protective immunity, respectively. The receptor-based mechanisms by which DCs recognize and respond to biomaterials is unknown, however commonalities between the cytokine, integrin, and pattern recognition receptor(PRR)-induced cellular responses and biomaterial-induced DC maturation, suggest that DCs engage a combination of these external sensing receptor families to initiate phenotypic responses to biomaterials. Our overall hypothesis is that DCs recognize and respond to biomaterial stimuli using a combination of receptors, necessitating an integrative modeling approach to establish multiple receptor ligation signatures associated with DC phenotypes. The objectives of this proposal are to 1) develop a model of how DCs integrate information from multiple receptor families concurrently to elicit phenotypic plasticity and 2) use this model to elucidate the key receptor families used by DCs to recognize and respond to biomaterials. We will achieve an integrative understanding with a global view of DC responses to biomaterials, including synergistic interactions, which is not feasible looking at one pathway at a time. The approach used in this proposal is to treat the DC as a system with delivered stimuli/inputs, sampled intermediate signals, and measured outputs/responses to develop a statistical model. This proposal thus applies a previously employed systems biology approach, developed by Lauffenberger, Janes and Kemp, in a novel capacity of addressing the "inverse" problem of identifying receptors used by DCs to sense biomaterials. Specific aim 1 will establish an integrative model of signaling and cytokine profiles for known receptor-driven DC phenotypic outcomes. Specific aim 2 will identify the receptor basis for DC responses to specific biomaterials. Specific aim 3 will validate role of receptor families mediating DC responses to specific biomaterials. Completion of this project will provide a framework for informed engineering DC-driven immune responses in the context of biomaterials for future studies. It will also provide a context for in-depth study of individual receptors with a dominant role in DC responses to biomaterials. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Our vision is to engineer specific immune cell interactions through biomaterials for use in immunomodulatory combination products to further the promise of tissue engineered constructs and vaccine delivery systems for treating and preventing human disease. This proposal applies a rigorous systems biology approach to elucidate the integrative mechanism of immune cell interactions with biomaterials to direct immune responses.